Implantable Prosthesis With Depot Retention Feature

ABSTRACT

A prosthesis for intraluminal drug delivery can comprise a plurality of interconnected struts that form a tubular scaffold structure. The struts include through-holes with an inner surface configured to retain a bioabsorbable depot. The bioabsorbable depot includes a drug-polymer composition that hydrolytically degrades upon implantation. The inner surface of the through-hole can be an entirely smooth and continuous area that is concave or convex, with no geometric discontinuities. The inner surface of the through-hole can include any number of constricted and distended regions to form grooves of a size and shape carefully selected to engage a corresponding geometric feature of the bioabsorbable depot.

FIELD OF THE INVENTION

Briefly and in general terms, the present invention generally relates toan implantable prosthesis and, more particularly, to a drug elutingstent.

BACKGROUND OF THE INVENTION

In percutaneous transluminal coronary angioplasty (PTCA), a ballooncatheter is inserted through a brachial or femoral artery, positionedacross a coronary artery occlusion, and inflated to compress againstatherosclerotic plaque to open, by remodeling, the lumen of the coronaryartery. The balloon is then deflated and withdrawn. Problems with PTCAinclude formation of intimal flaps or torn arterial linings, both ofwhich can create another occlusion in the lumen of the coronary artery.Moreover, thrombosis and restenosis may occur several months after theprocedure and create a need for additional angioplasty or a surgicalbypass operation. Stents are used to address these issues. Stents aresmall, intricate, implantable medical devices and are generally leftimplanted within the patient to reduce occlusions, inhibit thrombosisand restenosis, and maintain patency within vascular lumens such as, forexample, the lumen of a coronary artery.

The treatment of a diseased site or lesion with a stent involves bothdelivery and deployment of the stent. Stent delivery refers tointroducing and transporting the stent through an anatomical lumen to adesired treatment site, such as a lesion in a vessel. An anatomicallumen can be any cavity, duct, or a tubular organ such as a bloodvessel, urinary tract, and bile duct. Stent deployment corresponds toexpansion of the stent within the anatomical lumen at the regionrequiring treatment. Delivery and deployment of a stent are accomplishedby positioning the stent about one end of a catheter, inserting the endof the catheter through the skin into an anatomical lumen, advancing thecatheter in the anatomical lumen to a desired treatment location,expanding the stent at the treatment location, and removing the catheterfrom the lumen with the stent remaining at the treatment location. Thesestents may be constructed of a fine mesh network of struts, whichprovide support or push against the walls of the anatomical lumen inwhich the stent is implanted.

In the case of a balloon expandable stent, the stent is mounted about aballoon disposed on the catheter. Mounting the stent typically involvescompressing or crimping the stent onto the balloon prior to insertion inan anatomical lumen. At the treatment site within the lumen, the stentis expanded by inflating the balloon. The balloon may then be deflatedand the catheter withdrawn from the stent and the lumen, leaving thestent at the treatment site. In the case of a self-expanding stent, thestent may be secured to the catheter via a retractable sheath. When thestent is at the treatment site, the sheath may be withdrawn which allowsthe stent to self-expand.

Stents are often modified to provide drug delivery capabilities tofurther address thrombosis and restenosis. Stents may be coated with apolymeric carrier impregnated with a drug or therapeutic substance. Aconventional method of coating includes applying a composition includinga solvent, a polymer dissolved in the solvent, and a therapeuticsubstance dispersed in the blend to the stent by immersing the stent inthe composition or by spraying the composition onto the stent. Thesolvent is allowed to evaporate, leaving on the stent strut surfaces acoating of the polymer and the therapeutic substance impregnated in thepolymer.

The application of a uniform coating with good adhesion to a substratecan be difficult for small and intricate medical devices, such ascertain stents for coronary and peripheral arteries. Such stents can bequite small. Stents for the coronary vessel anatomy typically have anoverall diameter of only a few millimeters and a total length of severalmillimeters to tens of millimeters. Stents for the peripheral vesselanatomy are generally greater in diameter and length. Such peripheralstents may have a diameter up to 10 mm and a length of up to a fewhundred millimeters.

Some drug eluting stents include pockets or depressions which are filledwith a drug-containing composition, referred to as a depot ormicrodepot. Depending on their size, the drug-containing compositionsmay cause an embolic hazard if they dislodge as particles from the stentand flow into a patient's blood stream. This can be of particularconcern for drug-containing compositions composed of bioabsorbablepolymers with mechanical properties that are altered by thebioabsorption process after implantation. Accordingly, there is a needfor stent designs that retain the microdepots.

SUMMARY OF THE INVENTION

Briefly and in general terms, the present invention is directed to animplantable, intraluminal prosthesis and a method of making aprosthesis.

In aspects of the present invention, an implantable, intraluminalprosthesis comprises a plurality of interconnected struts and aplurality of bioabsorbable depots. The plurality of interconnectedstruts form a tubular structure, each of the struts having a luminalsurface facing radially inward and an abluminal surface facing radiallyoutward. At least some of the struts have through-holes with oppositeend openings located at the abluminal and luminal surfaces. Each of thethrough-holes has an inner surface with a geometric retention feature ata middle segment of the through-hole. The geometric feature has apredetermined shape corresponding to a distention of the through-hole orcorresponding to a constriction of the through-hole. Each bioabsorbabledepot is carried in a separate one of the through-holes, wherein thegeometric retention feature of each of the through-holes is configuredto retain the bioabsorbable depot in the through-hole after a decreasein molecular weight, strength or mass of the bioabsorbable depot.

In aspects of the present invention, an implantable, intraluminalprosthesis comprises a tubular frame of interconnected structuralmembers. The tubular frame is configured to expand radially. At leastsome of the structural members have a through-hole formed therein, eachthrough-hole comprising two end openings and an inner surface extendingbetween the end openings, the inner surface having an indentation of apreselected size and shape. The prosthesis further comprises a pluralityof bioabsorbable depots, each bioabsorbable depot retained in a separateone of the through-holes. Each bioabsorbable depot comprises atherapeutic agent and a bioabsorbable polymer. Each bioabsorbable depotcomprises a protrusion that extends into the indentation of thethrough-hole in which the bioabsorbable depot is retained. Theprotrusion and the indentation engaged with each other to prevent thebioabsorbable depot from sliding out of at least one of the endopenings.

In aspects of the present invention, a method of making an implantable,intraluminal prosthesis comprises forming a tubular frame ofinterconnected structural members, forming through-holes in thestructural members, and forming an indentation in an inner surface ofeach of the through-holes. The method further comprises forming abioabsorbable depot in each of the through-holes, which comprisesforming a protrusion of the bioabsorbable depot that engages theindentation of the through-hole in which the bioabsorbable depot isretained. Engagement of the protrusion with the indentation prevents thebioabsorbable depot from sliding out of the through-hole.

The features and advantages of the invention will be more readilyunderstood from the following detailed description which should be readin conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a is a perspective view of an end portion of a stent.

FIGS. 2 and 3 are perspective and radial cross-sectional views,respectively, of a stent.

FIG. 4 is a radial cross-sectional view of a stent, showing stent strutswith transverse through-holes for carrying a therapeutic agent to bedelivered intraluminally.

FIG. 5 is a radial cross-sectional view of a stent, showing stent strutswith axial through-holes for carrying a therapeutic agent.

FIG. 6 is a radial cross-sectional view of a stent, showing stent strutswith radial through-holes for carrying a therapeutic agent.

FIG. 7 is a radial cross-sectional view of a prosthesis structuralmember, showing a single through-hole that may be oriented radially,axially, or transversely, the through-hole having no depot retentionfeature.

FIG. 8 is a graph showing changes in parameter values over time, theparameter values being molecular weight, strength, and mass of abioabsorbable polymer.

FIGS. 9A-9D are radial cross-sectional views of a prosthesis structuralmember, showing a through-hole with a depot retention feature in theform of a smooth, continuously tapered inner surface.

FIGS. 10A-10E are perspective views of various bioabsorbable depots thatcan be retained in a through-hole having a smooth, continuously taperedinner surface.

FIGS. 11A and 11B are cross-sectional and perspective views,respectively, of a prosthesis structural member, showing a through-holewith a depot retention feature in the form of a constriction in a middlesegment of the through-hole.

FIGS. 12A-12E are perspective views of various bioabsorbable depots thatcan be retained in a through-hole having a constriction in a middlesegment of the through-hole.

FIGS. 13A and 13B are cross-sectional and perspective views,respectively, of a prosthesis structural member, showing a through-holewith a depot retention feature in the form of a distension in a middlesegment of the through-hole, the distension created by an indentation inan inner surface of the through-hole.

FIGS. 14A-14E are perspective views of various bioabsorbable depots thatcan be retained in a through-hole having a distension in a middlesegment of the through-hole.

FIGS. 15A and 15B are cross-sectional views of a prosthesis structuralmember and a bioabsorbable depot, respectively, the views showing agroove formed in an inner surface of the through-hole for receiving andengaging a tang protruding from the bioabsorbable depot.

FIGS. 15C-15F are cross-sectional views of a prosthesis structuralmember, showing various groove geometries for retaining a bioabsorbabledepot.

FIGS. 16A-16D are perspective views of various bioabsorbable depots thatcan be retained in the through-hole of FIG. 15A.

FIG. 17 is perspective view of a portion of a stent in an expandedstate, showing laser beams making through-holes in the stent struts withshields protecting adjacent stent struts from the laser beams.

FIGS. 18A-18D are cross-sectional views of a prosthesis structuralmember, showing various stepped geometries for retaining a bioabsorbabledepot, the geometries including tapered, convex, and notched innersurfaces of a through-hole.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring now in more detail to the exemplary drawings for purposes ofillustrating embodiments of the invention, wherein like referencenumerals designate corresponding or like elements among the severalviews, there is shown in FIG. 1 an upper portion of a stent 10 having anoverall body shape that is hollow and tubular. The stent can be balloonexpandable or self-expandable.

The present invention encompasses stents having any particulargeometrical configuration, such as a zig-zag, sinusoidal or serpentinestrut configuration, and should not be limited to the patternsillustrated herein. The variation in stent patterns is virtuallyunlimited.

FIGS. 1 and 2 show stents with two different stent patterns. The stentsare illustrated in an uncrimped or expanded state. In both FIGS. 1 and 2the stent 10 includes many interconnecting struts 12 a, 12 b separatedfrom each other by gaps 16. The struts 12 a, 12 b form a tubular frameand can be made of any suitable material, such as a biocompatible metalor biocompatible polymer. The material can be non-bioabsorable orbioabsorbable.

As used herein, the terms “bioabsorbable” and “biodegradable” are usedinterchangeably and refer to materials that are capable of beingdegraded or absorbed when exposed to bodily fluids such as blood, andcomponents thereof such as enzymes, and that can be gradually resorbed,absorbed, and/or eliminated by the human or animal body.

The stent 10 has an overall longitudinal length 40 measured fromopposite ends, referred to as the distal and proximal ends 22, 24. Thestent 10 has an overall body 50 having a tube shape with a centralpassageway 17 passing through the entire longitudinal length of thestent. The central passageway has two circular openings, there being onecircular opening at each of the distal and proximal ends 22, 24 of theoverall tubular body 50. A central axis 18 runs through the centralpassageway in the center of the tubular frame or body 50. At least someof the struts 12 a are arranged circumferentially in series to formsinusoidal or serpentine ring structures 20 that encircle the centralaxis 18. The ring structures 20 are connected to each other by otherstruts 12 b, referred to as links, that are substantially straight andare oriented longitudinally. In some embodiments, the ring structures 20are configured to be crimped and subsequently radially expanded. In someembodiments, the ring structures 20 are connected directly to oneanother without intervening links 12 b.

FIG. 3 is an exemplary radial cross-sectional view of the stent 10 alongline 2-2 in FIG. 2. There can be any number of struts 12 along line 2-2,which runs perpendicular to the central axis 18 of the stent 10. In FIG.3, the cross-section of seven struts 12 are shown for ease ofillustration. The struts 12 in cross-section are arranged in a circularpattern having an outer diameter 26 and an inner diameter 28. Thecircular pattern encircles the central axis 18. A portion of the surfaceof each strut faces radially inward in a direction 30 facing toward thecentral axis 18. A portion of the surface of each strut faces radiallyoutward in a direction 32 facing away from the central axis 18. Thevarious strut surfaces that face radially outward are individuallyreferred to as abluminal surfaces 34. The abluminal surfaces of thestruts collectively form the abluminal surface of the stent tubular body50. The various strut surfaces that face radially inward areindividually referred to as luminal surfaces 36. The luminal surfaces ofthe struts collectively form the luminal surface of the stent tubularbody 50. Side surfaces 38 connect the luminal surfaces 36 to theabluminal surfaces 34. In FIG. 3, the side surfaces 38 are flat andextend radially.

The terms “axial” and “longitudinal” are used interchangeably and relateto a direction, line or orientation that is parallel or substantiallyparallel to the central axis of a stent or a central axis of acylindrical or tubular structure. The term “circumferential” relates tothe direction along a circumference of a stent or a circular structure.The terms “radial” and “radially” relate to a direction, line ororientation that is perpendicular or substantially perpendicular to thecentral axis of a stent or a central axis of a cylindrical or tubularstructure.

As shown for example in FIGS. 4-6, at least some of the struts can havethrough-holes 50. The through-holes 50 are different from the gaps 16(FIGS. 2 and 3) in that the through-holes 50 are formed into individualstruts 12 whereas the gaps 16 are disposed between two of more of thestruts 12. Also, the gaps 16 change greatly in size during crimping andradial expansion of the stent body whereas the through-holes 50 do notchange in size as a result of crimping and radial expansion of the stentbody. Further, the through-holes 50 have a cross-dimension or diameterthat is no greater than the cross-dimension or width of an individualstrut, whereas the gaps 16 have a cross-dimension that often exceedsthat of the struts.

The term “through-hole” refers to a passageway that extends entirelythrough a structure and has openings at opposite ends of the passageway.Through-holes can be straight with no bend, as shown in FIGS. 4-6, orthey can be slightly curved or bent. Through-holes are different fromblind-holes which have only a single opening and do not extend entirelythrough a structure. Each of the through-holes shown in FIGS. 4-7, 11A,13A, 15A and 18A have exactly two openings and do not connect to orintersect with any other through-hole. In some embodiments, athrough-hole intersects with or extends into another through-hole.

In some embodiments, the openings at opposite ends of the through-holes50 have a diameter from 10 microns to 300 microns, and more narrowlyfrom 40 microns to 200 microns. In some embodiments, the through-holeshave an average diameter across the entire length of the through-holesfrom 10 microns to 300 microns, and more narrowly from 40 microns to 200microns.

In some embodiments, as shown in FIG. 4, through-holes 50 are orientedtransversely or extend transversely through the struts 12. Each of thetransverse through-holes 50 has an end-to-end inline length 52 thatextends in a transverse direction 54. The phrase “transverse direction”refers to a direction that runs substantially at a tangent to a circlearound the central axis 18 and which does not intersect the central axis18. The term “end-to-end inline length” refers to a straight linesegment that starts from the center of one through-hole opening, ends atthe center of the opposite through-hole opening, and runs through thethrough-hole passageway without intersecting walls of the through-hole.As shown in FIG. 4, the transverse through-holes pass through sidesurfaces 38 that face in opposite directions. In other embodiments, allor only some of the through-holes in an implantable prosthesis areoriented transversely.

In some embodiments, as shown in FIG. 5, through-holes 50 are orientedaxially or extend axially through the struts 12. Each of the axialthrough-holes 50 has an end-to-end inline length that extends in anaxial direction that is substantially parallel to the central axis 18.The axial through-holes pass through side surfaces 38 that face inopposite axial directions. In other embodiments, all or only some of thethrough-holes in an implantable prosthesis are oriented axially.

In some embodiments, as shown in FIG. 6, through-holes 50 are orientedradially or extend radially through struts 12. Each of the radialthrough-holes 50 has an end-to-end inline length 52 that extends in aradial direction 58 away from the central axis 18. The radialthrough-holes pass through the abluminal surfaces 34 and luminalsurfaces 36 of the struts 12. In other embodiments, all or only some ofthe through-holes in an implantable prosthesis are oriented radially.

In some embodiments, where the implantable prosthesis is tubular, theend openings of the through-holes are located at the abluminal surfaceor luminal surface exclusively. In some embodiments, where theimplantable prosthesis includes interconnecting struts, the end openingsof the through-holes are located at the strut side surfaces exclusively.In other embodiments, an implantable prosthesis has a mix of radialthrough-holes and non-radial through-holes.

The through-holes described above and below are configured to carry abioabsorbable composition, referred to as a bioabsorbable depot 60, suchas shown in FIG. 7. The composition includes a drug which is releasedinto the anatomical lumen and vessel wall as the composition degradesover time.

In the above and following description, the word “drug” in the singularincludes the plural unless expressly stated otherwise. It is to beunderstood that the word “drug” includes one such drug, two such drugs,or under the right circumstances as determined by those skilled in thetreatment of diseased tissues, even more such drugs unless it isexpressly stated or is unambiguous from the context that such is notintended.

In some embodiments, the composition includes a bioabsorbable polymer inwhich the drug is dispersed, mixed, or encased. An example of such apolymer is poly(D,L-lactide-co-glycolide), also referred to as PLGA.After implantation of the prosthesis, the bioabsorbable depot couldbecome loose as shown in FIG. 7. This is because polymers that undergo ahydrolytic degradation mechanism, such as PLGA, lose molecular weight,mechanical strength, and mass over time, such as generally depicted inFIG. 8. It is apparent from FIG. 8 that the strength of the polymer willstart to diminish before mass loss takes place. As molecular weightdrops, the polymer gets weaker and weaker, essentially becoming softer.Also as the molecular weight drops, there is an increase in watercontent due to an increase in carboxyl and hydroxyl polymer endgroups.For PLGA, by the time that mass loss occurs at a significant rate, themolecular weight has dropped to as low as 20K Daltons, so that themicrodepot is a soft mass. Thus, a bioabsorbable depot may detach ordislodge if it is made of a bioabsorbable polymer.

A way to keep the bioabsorbable depot 60 from dislodging after softeningor loosing mass is to have through-holes that have variablecross-sections and geometric discontinuities. The variable cross-sectionresults from having inner walls of the through-holes be a particularconfiguration (e.g., as shown in FIGS. 9, 11, 13, 15 and 18) thatprevents or inhibits a bioabsorbable depot from dislodging as a particlehaving a size that could present an embolic hazard. The embolic hazarddepends on the number and size of released particles. As particle sizeincreases, the volume of tissue that is embolized by occlusion of distalvasculature rises in a non-linear, almost exponential fashion. Debris inthe blood stream that is 100 microns or more in size, in particular, canpresent an embolic hazard. Also, particles as small as 10 microns can behazardous if released in large numbers.

The various depot retention features described below can be applied toany of the through-holes shown in FIGS. 4-7.

In some embodiments, as shown in FIG. 9A, a through-hole 50A (shownwithout a bioabsorbable depot) has an inner surface 62A with a taperedcross-sectional configuration. As shown in FIG. 9B, a bioabsorbabledepot 60A inside the through-hole 50A takes on a corresponding taperedcross-sectional shape. There are two openings 64A, 66A at opposite endsof the through-hole 50A. One of the openings 66A is larger than theother 64A, so that the bioabsorbable depot is prevented or inhibitedfrom sliding out in the direction of arrow 68. The relatively narrowsegment of the through-hole, adjacent the smaller opening 64A, serves asa geometric retention feature that keeps the depot from sliding out inthe direction of arrow 68. In use as shown in FIG. 9C, the largeropening 66A is at an abluminal surface 34 of an implantable prosthesisso that the larger opening 66A is up against or immediately adjacent ananatomical structure 70, such as blood vessel wall, so as to keep thebioabsorbable depot 60A from sliding out in the direction of arrow 72.The smaller opening 64A can be sized such that after significant loss orstrength and/or mass over time, as shown in FIG. 9D, the bioabsorbabledepot 60A cannot pass through the smaller opening 64A and is retained inthe tapered through-hole 50A.

In some embodiments, the cross-dimension 84 of the smaller opening 64Ais from about 10 microns to 200 microns, more narrowly from about 10microns to 100 microns, more narrowly from about 10 microns to about 80microns, and more narrowly from about 10 microns to about 50 microns.The upper size limit for the cross-dimension 84 is optionally below 100microns since debris of 100 microns or more in size may present aparticular embolic hazard. In some embodiments, the cross-dimension 84of the smaller opening 64A is at least half that of the cross-dimension86 of the larger opening 66A, giving a size ratio of 1:2. Other suitablesize ratios include without limitation 1:3, 1:4, 1:5, and 1:10.

The inner surfaces 62A of a tapered through-hole 50A and thecorresponding bioabsorbable depot 60A can take a number of shapes. FIGS.10A-10E show various bioabsorbable depots 60A and it is to be understoodthat the inner surfaces of the tapered through-hole 50A has acorresponding negative shape to that shown in FIGS. 10A-10E. The taperedbioabsorbable depot 60A in FIGS. 9B-9D can have any of thethree-dimensional shapes shown in FIGS. 10A-10D. The narrow end 74 ofthe bioabsorbable depot 60A corresponds in shape and dimension to thesmaller opening 64A of the tapered through-hole 50A. The broader end 76of the bioabsorbable depot 60A corresponds in shape and dimension to thelarger opening 66A of the tapered through-hole 50A. The side surfaces 78of the bioabsorbable depot 60A corresponds in shape and dimension to theinner surface 62A of the tapered through-hole 50A. Suitable taperedshapes include without limitation: a four-sided pyramidal shape as shownin FIG. 10A wherein none of the side surfaces 78 are parallel to anotherside surface; a three-sided pyramidal shape as shown in FIG. 10B; atrapezoidal shape as shown in FIG. 10C wherein two oppositely disposedside surfaces 78 a, 78 b are parallel to each other; a truncated coneshape as shown in FIG. 10D; and a truncated sphere shape as shown inFIG. 10E.

In some embodiments, as shown in FIGS. 11A and 11B, a constrictedthrough-hole 50B (shown in FIG. 11A without a bioabsorbable depot) hasan inner surface 62B with a depot retention feature in the form of ageometric constriction 80B between the opposite end openings 64B, 66B ofthe constricted through-hole 50B. As shown in FIG. 11A, the constriction80B has a linear cross-dimension 82 that is smaller than the linearcross-dimensions 84, 86 of the end openings 64B, 66B. As shown in FIG.11B, the constriction 80B has a planar cross-area 88 that is smallerthan the planar cross-areas 90, 92 of the end openings 64B, 66B. Forclarity in FIG. 11B, a prosthesis structural member 12, such as a stentstrut, is illustrated as translucent with broken lines and thecross-areas are illustrated with hatch lines. As used herein, the“linear cross-dimension” and the “planar cross-area” are by definitionperpendicular or substantially perpendicular to the end-to-end inlinelength 52 (illustrated as a broken line in FIG. 11A) of thethrough-hole. As indicated by the inline length 52 shown in FIG. 11A,the through-hole 50B extends end-to-end along a straight line.

Referring to FIG. 11A, the through-hole 50B includes end segments 93B,97B at the opposite end openings 64B, 66B and a middle segment 95Bbetween the end segments 93B, 97B. The geometric constriction 80B islocated at the middle segment 95B and protrudes into the through-holepassageway. Indentations of the through-hole inner surface 62B arelocated above and below the geometric constriction 80B, at the oppositeend openings 64B, 66B.

In some embodiments, the cross-dimension 82 of the constriction is fromabout 10 microns to 200 microns, more narrowly from about 10 microns to100 microns, and more narrowly from about 5 microns to about 50 microns.The upper size limit for the constriction cross-dimension is preferablybelow 100 microns since debris of 100 microns or more in size maypresent a particular embolic hazard, which may then allow the openingcross-dimensions to be substantially greater than 100 microns. In someembodiments, the cross-dimension 82 of the constriction is at least halfthat of the cross-dimensions 84, 86 of the end opening, which gives anconstriction-to-opening size ratio of 1-to-2. Other suitable ratiosinclude without limitation 1-to-5,1-to-4,1-to-3,2-to-3,3-to-4, and4-to-5.

In use, any one of the end openings 64B, 66B of the constrictedthrough-hole 50B can be up against or immediately adjacent an anatomicalstructure, such as blood vessel wall. In FIG. 11A, the larger opening66B of the through-hole 66B is located on the abluminal side of theprosthesis to allow delivery of a greater amount of a drug to a vesselwall. In other embodiments, the larger opening 66B of all or some of thethrough-holes 66B of a tubular intraluminal prosthesis can be located onthe luminal side to allow delivery of a greater amount of a drug into afluid stream passing through the central passageway of the prosthesis.In this way, the concentration of drug that is released from theprosthesis can be controlled and customized as desired.

The inner surfaces 62B of a constricted through-hole 50B and thecorresponding bioabsorbable depot 60B can take a number of shapes. FIGS.12A-12E show various bioabsorbable depots 60B and it is to be understoodthat the inner surfaces of a constricted through-hole has acorresponding negative shape to that shown in FIGS. 12A-12E. The broadends 74, 76 of the bioabsorbable depot 60B correspond in shape anddimension to the end openings of the constricted through-hole. The sidesurface 78 of the bioabsorbable depot 60B corresponds in shape anddimension to the inner surface of the constricted through-hole. Forexample, a smooth concave shape on the depot corresponds to a smoothconvex shape on the inner surface of the through-hole, and vice versa.Suitable shapes include without limitation: a double pyramid as shown inFIG. 12A; a double truncated sphere as shown in FIG. 12B wherein twosmooth concave surfaces meet at the constriction; a cylindrical concaveshape as shown in FIG. 12C wherein a single concave sweep curve rotated360 degrees defines the entire side surface 78; a double-concave bar asshown in FIG. 12D wherein only two side surfaces 78 a, 78 b are smoothand concave and the other side surfaces are planar; and a single-concavebar as shown in FIG. 12E wherein only one side surface 78 a is smoothand concave and the other side surfaces are planar. The bioabsorbabledepot 60B of FIG. 12A fits within the constricted through-hole 50B ofFIGS. 11A and. 11B.

In some embodiments, as shown in FIGS. 13A and 13B, a dilated ordistended through-hole 50C (shown in FIG. 13A without a bioabsorbabledepot) has an inner surface 62C with a depot retention feature in theform of a geometric distension 80C between the opposite end openings64C, 66C of the distended through-hole 50C. As shown in FIG. 13A, thedistension 80C has a linear cross-dimension 86 that is greater than thelinear cross-dimensions 82, 84 of the end openings 64C, 66C. As shown inFIG. 13B, the distension 80C has a planar cross-area 88 that is largerthan the planar cross-areas 90, 92 of the end openings 64C, 66C. Forclarity in FIG. 13B, a prosthesis structural member 12, such as a stentstrut, is illustrated as translucent with broken lines and thecross-areas are illustrated with hatch lines. As used herein, the“linear cross-dimension” and the “planar cross-area” are by definitionperpendicular or substantially perpendicular to the end-to-end inlinelength 52 (illustrated as a broken line in FIG. 13A) of thethrough-hole. As indicated by the inline length 52 shown in FIG. 13A,the through-hole 50C extends end-to-end along a straight line. In use,any one of the narrow end openings 64C, 66C of the constrictedthrough-hole 50C can be up against or immediately adjacent an anatomicalstructure, such as blood vessel wall.

Referring to FIG. 13A, the through-hole 50C includes end segments 93C,97C at the opposite end openings 64C, 66C and a middle segment 95Cbetween the end segments 93C, 97C. The geometric distension 80C, whichcan be described as an indentation of the through-hole inner surface62C, is located at the middle segment 95C. The inner surface 62Cprotrudes inward toward the through-hole passageway, above and below thegeometric distension 80C, at the opposite end openings 64C, 66C.

In some embodiments, both of the cross-dimensions 82, 84 of the endopenings 64C, 66C are from about 10 microns to 200 microns, morenarrowly from about 10 microns to 100 microns, and more narrowly fromabout 5 microns to about 50 microns. The upper size limit for theopenings is optionally below 100 microns since debris of 100 microns ormore in size may present a particular embolic hazard, which may thenallow the distension cross-dimensions 86 to be substantially greaterthan 100 microns. In some embodiments, the distension cross-dimensions86 is about 50 microns, or about 120 microns, or about 150 microns, orabout 200 microns. In some embodiments, the opening cross-dimensions 82,84 are at least half that of the distension cross-dimension 86, giving asize ratio of 1:2. Other suitable ratios include without limitation 1:4,1:8 and 1:10.

The inner surfaces 62C of a distended through-hole 50C and thecorresponding bioabsorbable depot 60C can take a number of shapes. FIGS.14A-14E show various bioabsorbable depots 60C and it is to be understoodthat the inner surface of a distended through-hole has a correspondingnegative shape to that shown in FIGS. 14A-14E. The narrow ends 74, 76 ofthe bioabsorbable depot 60C correspond in shape and dimension to endopenings of the distended through-hole. The side surface 78 of thebioabsorbable depot 60C corresponds in shape and dimension to the innersurface of the distended through-hole. For example, a protrusion on thedepot corresponds to an indentation on the inner surface of thethrough-hole, and vice versa. Suitable shapes include withoutlimitation: a double pyramid as shown in FIG. 14A; a truncated sphere asshown in FIG. 14B; a cylindrical convex shape as shown in FIG. 14Cwherein a convex sweep curve rotated 360 degrees defines the entire sidesurface 78; a double-convex bar as shown in FIG. 14D wherein only twoside surfaces 78 a, 78 b are convex and the other side surfaces areplanar; and single-convex bar as shown in FIG. 14E wherein only one sidesurface 78 a is convex and the other side surfaces are planar. Thebioabsorbable depot 60C of FIG. 14A fits within the distendedthrough-hole 50C of FIGS. 13A and 13B.

A depot retention feature of a through-hole 50 can be an indentation,groove, or depression in an inner surface of the through-hole. Anindentation, groove, and depression with an abrupt change in geometrycan be referred to as a notch retention feature 80D, which forms anotched inner surface 62, such as shown in FIG. 15A. Unlike randomlydistributed pits and asperities of a rough surface, such as typicallyoccurs with sintered materials, the depot retention features of thepresent invention are distributed in an ordered pattern in the innersurface of a through-hole or located in preselected areas on the innersurface. The location of pits and asperities of a sintered material andother rough surfaces are not selected, which could make such pits andasperities less reliable for depot retention. Also, the retentionfeatures of the present invention have a preselected shape,configuration, and dimension, which can make them more reliable fordepot retention than pits and asperities having random sizes and shapes.For example, all the through-holes of an implantable prosthesis can eachhave a geometric retention feature that is identical or substantiallyidentical for all the through-holes with respect to size, shape,dimension and/or location on the through-hole inner surface.

In some embodiments, as shown in FIG. 15A, a through-hole 50D has anotched inner surface 62D with a rectangular groove 80D formed therein.A bioabsorbable depot 60D is illustrated separately in FIG. 15B forclarity. It is to be understood that the bioabsorbable depot 60D (notillustrated in FIG. 15A) is disposed within the through-hole 50D. Thebioabsorbable depot 60D can be in direct contact with the entire innersurface 62D of the through-hole 50D with no gaps. The inner surface 62Dof the through-hole 50C has a corresponding negative shape to that shownfor the bioabsorbable depot 60D. The bioabsorbable depot 60D has atongue or tang 96 that protrudes out from the remainder of the depot.The tang 96 fits within and contacts the interior of the groove 80D toprevent the depot from sliding out of the through-hole.

The cross-sectional shape for the bioabsorbable depot 60D of FIG. 15Bcan apply to any number of three-dimensional depot shapes, such as shownin FIGS. 16A-16D. Where the through-hole 50D is rectangular orfour-sided, the groove 80D can sweep or extend through all four sides ofthe through-hole, as indicated by the shape of the corresponding tang 96of the bioabsorbable depot 60D of FIG. 16A. Alternatively, the groove80D can sweep or extend linearly through only two sides of a four-sidedthrough-hole, as indicated by the shape of the corresponding tang 96 ofthe bioabsorbable depot 60D of FIG. 16B. It is also contemplated thatthe groove 80D can extend through only one side of the through-hole.

Where the through-hole 50D is circular or round, the groove 80D cansweep 360 degrees, entirely around a central passageway of thethrough-hole, as indicated by the shape of the corresponding circulartang 96 of the bioabsorbable depot 60D of FIG. 16C. Alternatively, thegroove 80D can be a rectangular slot formed into a curved inner surface62D of a circular through-hole 50D, as indicated by the bar-shaped tang96 of the bioabsorbable depot 60D of FIG. 16D.

Referring again to FIG. 15A, the through-hole 50D comprises constrictedregions or volumes 98 a, 98 b at both ends of the through-hole. Arelatively broad or distended region or volume 100 is disposed betweenthe constricted volumes 98. The constricted volumes 98 a, 98 b each havea preselected length or inline-dimension 102 a, 102 b, and a preselectedwidth or cross-dimensions 106 a, 106 b. The distended volume 100 has apreselected length or inline-dimension 104 and a preselected width orcross-dimension 108. As used herein, each “inline-dimension” is measuredalong a straight line that is parallel to the central axis 107 of thethrough-hole, the central axis being a straight line running through therespective centers of the end openings 64 d, 66 d of the through-hole.Each “cross-dimension” is measured along a straight line that isperpendicular to the central axis 107. As indicated by the axis 107shown in FIG. 15A, the through-hole 50D is symmetrical from side-to-sideand extends end-to-end along a straight line.

As shown in FIG. 15A, the inline-dimension 104 of the distended volume100 and the inline-dimensions 98 a, 98 b of the constricted volumes 98a, 98 b are substantially equal to each other. As shown in FIG. 15C, tofacilitate greater retention capability and/or to carry more therapeuticagent in the bioabsorbable depot, the through-hole 50D can be configuredsuch that the inline-dimension 104 of the distended volume 100 issubstantially greater than the inline-dimensions 98 a, 98 b of theconstricted volumes 98 a, 98 b. In this way, the distended volume 100can be two, three, four or more times larger in volume than the combinedvolume of the constricted volumes 98 a, 98 b.

In some embodiments, both of the cross-dimensions 106 a, 106 b of theconstricted volumes 98 a, 98 b are from about 10 microns to 200 microns,more narrowly from about 10 microns to 100 microns, more narrowly fromabout 10 microns to about 80 microns, and more narrowly from about 10microns to about 50 microns. The upper size limit for the constrictedcross-dimension is optionally below 100 microns since debris of 100microns or more in size may present a particular embolic hazard, whichmay then allow the cross-dimensions 108 of the distended volume to besubstantially greater than 100 microns.

Referring again to FIG. 15A, the cross-dimension 108 of the distendedvolume 100 is about twice that of the cross-dimensions 106 a, 106 b ofthe constricted volumes 98 a, 98 b. As shown in FIG. 15C, to facilitategreater depot retention capability and/or to carry more therapeuticagent in the bioabsorbable depot, the through-hole 50D can be configuredsuch that the cross-dimension 108 of the distended volume 100 is aboutthree times greater than the cross-dimensions 106 a, 106 b of theconstricted volumes 98 a, 98 b, so as to provide aconstricted-to-distended volumetric ratio of 1-to-3. Other suitablevolumetric ratios include 3-to-4,2-to-3; 1-to-2, and 1-to-4.

As shown in FIG. 15A, the cross-dimensions 106 a, 106 b of theconstricted volumes 98 a, 98 b are substantially equal to each other. Inother embodiments, the cross-dimension of one of the constricted volumesis substantially less than the cross-dimension of the constricted volumeat the other end of the through-hole. This can facilitate greaterretention capability when the smaller cross-dimension is on the luminalsurface of an implanted tubular prosthesis and the largercross-dimension is on the abluminal side against an anatomical lumenwall.

FIGS. 15A and 15C show embodiments having only one distended volume 100in a through-hole 50D. In other embodiments, a through-hole can have anynumber of distended volumes separated from each other by constrictedvolumes so as to facilitate greater depot retention capability. As shownin FIG. 15D, for example, a through-hole 50D can have three distendedvolumes 100 a, 100 b, 100 c and four constricted volumes 98 a, 98 b, 98c, 98 b. This produces three sets of grooves 80D that are arranged in arepeating, non-random pattern in the inner surface of the through-hole50D.

In other embodiments, the rectangular cross-sectional shape of thegroove 80D as disclosed in FIGS. 15A, 15C and 15D can be replaced by anyone or a combination of other cross-sectional shapes, including but notlimited to a half-circle cross-sectional shape, a trapezoidcross-sectional shape, and a triangular cross-sectional shape such asthat of the groove 80D in FIG. 15E.

In FIG. 15E, the point of the triangle extends into the inner surface ofthe through-hole. The interior surfaces 81 of the groove 80D are atoblique angles to other parts of the inner surface 62D. The term“oblique angle” refers to a direction that is not perpendicular and notparallel to a referenced structure. By comparison, in FIG. 15A variousinterior surfaces 81 of the rectangular groove 80D are at right anglesor ninety-degree to other parts of the inner surface 62D.

Embodiments of the present invention include implantable prostheseshaving the through-holes described above wherein none, some, or all thethrough-holes are filled with a drug and/or drug-polymer composition. Insome embodiments, the bioabsorbable depot may comprise multiple layersof bioabsorbable polymer, and any one or both of drug composition andpolymer composition varies among the multiple layers. In otherembodiments, the bioabsorbable depot comprises multiple layers ofbioabsorbable polymer, and the bioabsorbable depot comprises drugs whichmay be in the same or different layers of the bioabsorbable polymer.

In some embodiments, a distended volume of the through-hole is filled oroccupied in part or entirely by a first layer of a bioabsorbable depot,and a constricted volume of the through-hole is occupied in part orentirely by a second layer the bioabsorbable depot. The second layeroptionally includes a bioabsorbable polymer that is either moreresistant or less resistant to hydrolytic degradation of its mechanicalproperties or loss of strength, mass and/or molecular weight than abioabsorbable polymer in the first layer. Either one or both of thefirst and second layers can contain a drug.

In some embodiments, a groove is filled or occupied in part or entirelyby a first layer of a bioabsorbable depot. The layer may optionallyinclude a bioabsorbable polymer that is either more resistant or lessresistant to hydrolytic degradation of its mechanical properties or lossof strength, mass and/or molecular weight than a bioabsorbable polymerin a second layer of the bioabsorbable depot. Either one or both of thefirst and second layers can contain a drug. The second layer may bedisposed entirely outside of the groove occupied by the first layer. Insome embodiments, a tang or a protrusion of a bioabsorbable depotincludes a bioabsorbable polymer that is more resistant to the abovedescribe degradation than a bioabsorbable polymer in another part of thebioabsorbable depot. In this way, retention of the bioabsorbable depotin the through-hole may be enhanced. In FIG. 15D, for example, each ofthe distended volumes 100 a, 100 b, 100 c can be filled by distinctlayers of the bioabsorbable depot, each layer including a bioabsorbablepolymer that is either more resistant or less resistant to the abovedescribed degradation than a bioabsorbable polymer in other distinctlayers that fill the constricted volumes 98 a, 98 b, 98 c.

The drug and/or drug-polymer composition can be deposited insidethrough-holes in a number of ways to form a stratified or multilayereddepot or, alternatively, a unitary depot. For example, an implantableprosthesis with through-holes can be immersed in, painted with, orsprayed with a liquid containing a desired drug. The liquid can be asolution of the drug and a biodegradable polymer dissolved in a solvent.The liquid is allowed to pass into the through-holes and allowed to dryat room temperature or at an elevated temperature above roomtemperature. A composition of the drug and polymer remains after thesolvent evaporates. The drug-polymer composition bonds or adheres to thewalls of the through-holes. Excess amounts of the composition can becleaned off all or some of the abluminal and/or luminal surfaces. Excessamounts of the composition can also be cleaned off all of the exteriorsurfaces (luminal, abluminal and side surfaces) of the implantableprosthesis so that the drug carried is carried exclusively in thethrough-holes.

Alternatively or in combination with the methods described above andbelow, drug and/or drug-polymer composition can be deposited into thethrough-holes by a method in which discrete droplets of liquid aredischarged such that each droplet travels in a controlled trajectory. Asystem and method for depositing droplets having a controlled trajectoryonto a stent is described in U.S. Pat. No. 7,208,190 to Verlee et al,which is incorporated herein by reference. In some embodiments, thecontrolled trajectory intersects selected abluminal, luminal, and sidesurfaces. In other embodiments, a feedback camera or optical device isimplemented to insure that the drug is deposited only on the sidesurfaces and in the through-holes, so that abluminal and luminalsurfaces are free of any drug. In other embodiments, the feedback cameraor optical device is implemented to insure that the drug is depositedonly in the through-holes, so that the drug is carried exclusively inthe through-holes. A method of controlling where a drug is deposited bymeans of a feedback camera or optical device is described in U.S. Pat.No. 6,395,326 to Castro et al., which is incorporated herein byreference.

Alternatively or in combination with the methods described above, a puredrug and/or drug-polymer composition may be directly injected as aliquid into a through-hole by a hollow microneedle. The microneedle canbe positioned immediately adjacent an end opening of the through-hole,then liquid of a predetermined volume from inside the microneedle can beforced into the through-hole. Alternatively or in combination withforced injection, the liquid from inside the microneedle can be drawn orimbibed into the through-hole by capillary action. For example, adroplet of liquid of a predetermined volume can be placed on an endopening of the through-hole, then capillary action brings the liquidinside through-hole.

The through-holes can be formed in the struts in a number of ways. Insome embodiments, a laser is used to vaporize or otherwise removematerial from the struts. The laser is aimed at a predetermined surfaceof a particular strut of a stent. To form a non-radial through-hole,such as a transverse or axial through-hole, the laser is aimed toward aside surface of a strut. To form a radial through-hole, the laser isaimed toward a luminal and/or abluminal surface of a strut. A lasersystem and method for making a stent is described in commonly owned U.S.Pat. No. 6,521,865 to Jones, et al., which is incorporated herein byreference.

After application of the laser, the resulting through-hole is bounded bythe base material or substrate material of the stent strut. The phrase“substrate material” refers to the material at the core of the stentstrut and does not include any coatings of other material added afterinitial formation of the core. The substrate material can be porous or,alternatively, substantially non-porous. The substrate material can be afused particulate material or, alternatively, a non-particulatematerial. Non-particulate substrate materials can be made by extrusion,molding, and/or casting processes that mix molten material to form asubstantially uniform and/or unitary core structure. By contrast, fusedparticulate materials are made up of discrete particles that are readilyidentifiable in the core structure after completion of the fusing step.

In some embodiments, each through-hole is bounded by or formed into aporous or particulate substrate material. A porous or particulatesubstrate material can be the result of particles of metal or polymerthat have been sintered or fused together such that small gaps or poresremain between the fused particles. The through-holes of the presentinvention are different from conventional pores, pits, and/or asperitiesbetween sintered particles. Such pores are not located at predeterminedpositions on a stent strut as they are randomly distributed betweenparticles. Also, such pores do not interconnect to form a channel orpassageway in a selected direction. In many instances, such pores merelycreate surface roughness or sealed air pockets with no channel orpathway that extends straight through a structure.

Particles and pores of a sintered stent substrate can have an averagediameter from submicron to tens of microns. In some embodiments, thethrough-holes formed into the stent substrate are several times largerin diameter than such pores. In some embodiments, the through-holes havean average diameter that is from 2 to 200 times larger than the averagediameter of the pores of a sintered material, and more narrowly from 10to 100 times larger than the average diameter of the pores of a sinteredmaterial, and more narrowly from 10 to 50 times larger than the averagediameter of the pores of a sintered material.

As shown in FIGS. 4 and 17, a laser beam 110 can be oriented in atransverse direction 112 relative to the central axis 18 of a stent toform a transverse through-hole. A shield 114, which can be in the formof a block of metal or ceramic, can be placed between the struts so thatthe laser beam forms a transverse through-hole in only a preselectedstrut and not in adjacent struts.

As shown in FIG. 17, a laser beam 116 can be oriented in a direction 118that is at a slight angle, such as 5 degrees to 30 degrees, from thecentral axis of the stent to form an axial through-hole. Depending onthe location of the strut, the laser beam can oriented at a directionthat is substantially parallel to the stent central axis in order toform axial through-holes. A shield 120, which can be in the form of ametal or ceramic plate, can be placed between the struts so that thelaser beam forms an axial through-hole in only a preselected strut andnot in adjacent struts.

As shown in FIGS. 6 and 17, a laser beam 122 can be oriented in a radialdirection 124 relative to the central axis 18 of a stent to form radialthrough-holes. A shield 126, which can be in the form of a metal rod,can be placed in the central passageway of the stent so that the laserbeam forms a radial through-hole in only a preselected strut and not inother struts.

Various laser machining parameters can be tuned or adjusted in order toform the geometric retention feature of the through-hole. The angle ofthe laser beam to the surface being modified can be adjusted or selectedto create the desired through-hole shape. The aspect ratio of the laserbeam can be adjusted or selected to have a different width as a functionof penetration into structure being modified. The direction, flow, andpressure of the gas being used to assist the laser cutting can also beadjusted. Any one or a combination of the above described parameters(e.g., laser angle, laser aspect ratio, gas direction, gas flow, gaspressure) can be adjusted or selected such that an inner surface of thethrough-hole is formed with any number of characteristics, including butnot limited to tapered, concave, convex, notched, stepped, smooth,circular, and planar.

For example, as shown in FIG. 15F, a laser beam 123 can be applied invarious directions at one region of a substrate material 12 to form agroove or distended volume in a through-hole 50 d. A first laser beam123 a is used to form a first inner surface of the through-hole. Asecond laser beam 123 b is used to form a second inner surface of thethrough-hole. A third laser beam 123 c is used to form a third innersurface of the through-hole. A fourth laser beam 123 d is used to form afourth inner surface of the through-hole. Also, multiple laser beams canbe applied simultaneously at one region of a substrate material 12 toform a groove or distended volume in a through-hole 50 d. Also, a singlelaser beam can be directed into an abluminal surface 34 and rotated ortilted (from 123 c to 123 d) to form a plurality of inner surfaces,followed by or contemporaneously with another laser beam directed into aluminal surface 36 that is rotated or tilted (from 123 a to 123 b) toform another plurality of inner surfaces.

Alternatively, or in combination with any of the techniques describedabove and below, through-holes can be formed by electropolishing. Forexample, a through-hole formed by laser machining, as described above,can be subjected to electropolishing to make one of the end openings ofthe through-hole larger than the opposite end opening.

Alternatively, or in combination with any of the techniques describedabove and below, through-holes can be formed by electric dischargemachining, also referred to as EDM. A method for creating features in animplantable prosthesis using EDM is described in commonly owned U.S.Pat. No. 7,537,610 to Reiss, which is incorporated herein by reference.An electrode and the prosthesis are electrically charged with oppositepolarities. The prosthesis can be mounted over a mandrel or othersupport device and submerged in a dielectric fluid. The electrode issubmerged in the dielectric fluid and brought into close proximity tothe surface of the implantable prosthesis to be modified with athrough-hole. A selected voltage level is applied across the electrodeand the prosthesis that will result in electric discharges that vaporizeor otherwise remove material from the surface of the prosthesis. Anelectrode having a selected tip shape can be used to form the desiredshape of the through-hole. The electrode tip can have a shape that is anegative of the desired through-hole shape, so that as the electrode tipmoves further and further below the prosthesis surface, inner surfacesof the through-hole attain the shape of the electrode tip.

The electrode tip can have any desired shape, including withoutlimitation, the shapes shown in FIGS. 10A-10E. For example, in a firststep, an electrode tip having the tapered, pyramid shape of FIG. 10A canbe directed toward an luminal surface 36 of an implantable prosthesis toform a first end opening 64 of a through-hole. Next, in a second step,the same or another electrode tip can be directed toward an abluminalsurface 34 at the same region of the prosthesis as in the first step.The second step forms a second end opening 66 directly opposite thefirst opening 64. In the second step, the electrode is moved deeper anddeeper into the substrate material 12 until the hole being formed meetswith the hole formed in the first step. The end result is theconstricted through-hole 50B of FIG. 11A. It is contemplated that two ormore electrodes can work simultaneously or sequentially on oppositesurfaces (e.g., abluminal and luminal surfaces, or two opposite sidesurfaces) of a prosthesis structural member to form a through-hole witha geometric feature for depot retention. During the electrical dischargeprocess, the one or more electrodes can be tilted and rotated inside athrough-hole. Such tilting and rotation, can for example, correspond tonumerals 123 a-123 e in FIG. 15F. Tilting and rotation enables theformation of other shapes, such as the tapered through-hole 50A anddistended through-hole 50C of FIGS. 9A and 13A.

Alternatively, or in combination with any of the techniques describedabove and below, through-holes can be formed by etching a strutsubstrate material. The substrate material can be in the form of asheet. Applied onto the sheet is a removable mask layer having apredetermined pattern of openings that corresponds to a desired patternof non-radial through-holes. A chemical solution is applied so thatunmasked areas of the sheet can be etched or eroded by the chemical toform one or more open channels or grooves in the sheet that correspondsto the desired pattern of non-radial through-holes. The sheet withgrooves can be rolled up to form an inner layer of a tubular stent body.A second sheet of the substrate material can be used as an outer layerof the tubular stent body. After removal of the mask layer, the secondsheet can be laminated, bonded or adhered over the rolled-up sheet so asto cover the grooves. A method for laminating layers of material to forma tubular prosthesis is described in U.S. Pat. No. 7,335,227 to Jalisi,which is incorporated herein by reference. A desired pattern of stentstruts can be cut from the tube by a mechanical cutting tool or a laser.The resulting framework of interconnected struts will have the desiredthrough-hole shape. Alternatively, a pattern of stent struts can be cutfrom the flat sheet of the substrate material after the etching step butbefore the sheet is rolled. Also, a pattern of stent struts can be cutfrom a flat sheet of the substrate before the etching step.

Any number of etched sheets 130 can be laminated or bonded as describedabove to form a number of geometries for a depot retention feature. Thelaminated or bonded etched sheets 30 collectively form a multi-layersubstrate 12 of an implantable prosthesis, which is distinct from theunitary substrate of FIGS. 15A and 15C-15F. As shown in FIG. 18A, aplurality of sheets 130 a-130 e having progressively smaller holes canbe stacked on top of each other to form a tapered through-hole 50A. Asshown in FIG. 18B, a plurality of sheets 130 a-130 e having a variety ofhole cross-dimensions can be stacked and aligned so as to form a convexor constricted through-hole 50B. As shown in FIGS. 18C and 18D, aplurality of sheets having a variety of hole cross-dimensions can bestacked so as to form notches or grooves 80D in an inner surface of athrough-hole 50D. The sheets can have different thicknesses as shown inFIG. 18D.

In FIG. 18A-18D, the inner surfaces of the through-holes arenon-continuous in that the surfaces include abrupt changes in geometryor geometric discontinuities. The geometric discontinuities are arrangedin an ordered, predetermined pattern. In FIG. 18A, for example, thegeometric discontinuities form an inner surface with progressive stepsor ledges. The geometric discontinuities may be smoothed or eliminatedby secondary processing, such as electropolishing, in order to form asmooth and continuous inner surface, such as the tapered inner surfaceof FIG. 9A or a smooth concave or convex surface.

Alternatively, or in combination with the techniques described above, adirect rapid prototyping method can be employed to form a stent havingthe above-described through-holes. Rapid prototyping refers to methodsof automatically constructing three-dimensional objects from digitalinformation derived from a computer-aided design file. The deriveddigital information can be in the form of an “STL” file, which is a fileformat used by stereolithography machines and the like. Rapidprototyping methods can make fully functional, production-qualityobjects in addition to prototypes. One rapid prototyping method involvesdepositing discrete or continuous amounts of a substrate material inmultiple planar layers. The droplets adhere to each other so that eachplanar layer has a predetermined pattern of holes. The planar layers areformed successively on top of each other to build a three-dimensionaltubular frame of interconnected struts with through-holes. The planarlayers can, for example, correspond to numerals 130 a-130 e in FIGS.18A-18D. It will thus be appreciated that any number of planar layerscan be stacked and fused together to form various geometries forretaining a bioabsorbable depot. Rapid prototyping methods to form astent according to the present invention also includes a Metal PrintingProcess (MPP), such as described in U.S. Patent Application PublicationNo. 2008/0057102 (U.S. application Ser. No. 11/839,104), which isincorporated herein by reference.

Embodiments of the present invention include the above describedconfigurations of through-holes, with or without a drug within thethrough-holes, in combination with a coating layer containing a drug. Insome embodiments, the coating layer is on all external surfaces,including abluminal, luminal and side surfaces. In other embodiments,none of the coating layer is on any of the abluminal and luminalsurfaces, and the coating layer is on one or more side surfacesexclusively. In other embodiments, none of the coating layer is on anyof the abluminal surfaces, and the coating layer is on one or more sideand luminal surfaces. In other embodiments, none of the coating layer ison any of the luminal surfaces, and the coating layer is on one or moreof the side and abluminal surfaces.

It will be appreciated that through-holes can be provided in a number ofimplantable prostheses, including without limitation self-expandablestents, balloon-expandable stents, grafts, and stent-grafts. Animplantable prosthesis is a device that is totally or partly introduced,surgically or medically, into a patient's body. The duration ofimplantation may be essentially permanent, i.e., intended to remain inplace for the remaining lifespan of the patient; until the devicebiodegrades; or until the device is physically removed. An intraluminalprosthesis having through-holes can be configured for intraluminaldelivery of a drug and can be configured to be implanted by intraluminalmethods, such as by a catheter delivery device known in the art, or byother implantation methods.

An implantable medical device specifically designed and intended solelyfor the localized delivery of a therapeutic agent is within the scope ofthis invention. At present, a preferred implantable medical devicecomprises an intraluminal stent. Optionally, the stent has bare metal,uncoated struts having through-holes as described above, with adrug-polymer composition in the through-holes. The bare metal strutsoptionally have substantially smooth and non-porous external surfaces.

The substrate material of the prosthesis can be any suitable materialknown in the art of stents and other implantable devices. Substratematerials include without limitation nitinol or nickel-titanium alloyshaving shape memory and superelastic properties, other shape-memorymetal alloys or polymers, stainless steel (such as 316L),nickel-cobalt-chromium-molybdenum alloys (such as MP35N),cobalt-chromium-tungsten-nickel-iron alloys (such as L605 orchonichrome), titanium, and tantalum.

The drug carried within and/or on the prosthesis substrate material canbe any suitable therapeutic agent known in the art of stents and otherimplantable devices. The therapeutic agent can be in a substantiallypure form. The therapeutic agent can be mixed, dispersed, dissolved,encapsulated or otherwise carried in a polymer.

Therapeutic agents include without limitation an anti-restenosis agent,an antiproliferative agent, an anti-inflammatory agent, anantineoplastic, an antimitotic, an antiplatelet, an anticoagulant, anantifibrin, an antithrombin, a cytostatic agent, an antibiotic, ananti-enzymatic agent, an angiogenic agent, a cyto-protective agent, acardioprotective agent, a proliferative agent, an ABC A1 agonist, anantioxidant, a cholesterol-lowering agent, aspirin, anangiotensin-converting enzyme, a beta blocker, a calcium channelblocker, nitroglycerin, a long-acting nitrate, a glycoprotein IIb-IIIainhibitor or any combination thereof.

Examples of antiproliferative agents include, without limitation,actinomycins, taxol, docetaxel, paclitaxel, rapamycin,40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin, ABT-578, zotarolimus, everolimus,biolimus, novolimus, myolimus, deforolimus, temsirolimus, perfenidoneand derivatives, analogs, prodrugs, co-drugs and combinations of any ofthe foregoing.

Examples of anti-inflammatory agents include, without limitation, bothsteroidal and non-steroidal (NSAID) anti-inflammatory agents such as,without limitation, clobetasol, alclofenac, alclometasone dipropionate,algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenacsodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen,apazone, balsalazide disodium, bendazac, benoxaprofen, benzydaminehydrochloride, bromelains, broperamole, budesonide, carprofen,cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasonebutyrate, clopirac, cloticasone propionate, cormethasone acetate,cortodoxone, deflazacort, desonide, desoximetasone, dexamethasonedipropionate, diclofenac potassium, diclofenac sodium, diflorasonediacetate, diflumidone sodium, diflunisal, difluprednate, diftalone,dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium,epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen,fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone,fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin,flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate,morniflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone,olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone,paranyline hydrochloride, pentosan polysulfate sodium, phenbutazonesodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate,tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide,tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin(acetylsalicylic acid), salicylic acid, corticosteroids,glucocorticoids, tacrolimus, pimecrolimus and derivatives, analogs,prodrugs, co-drugs and combinations of any of the foregoing.

Examples of antineoplastics and antimitotics include, withoutlimitation, paclitaxel, docetaxel, methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, andmitomycin.

Examples of antiplatelet, anticoagulant, antifibrin, and antithrombindrugs include, without limitation, sodium heparin, low molecular weightheparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,prostacyclin, prostacyclin dextran, D-phe-pro-arg-chloromethylketone,dipyridamole, glycoprotein IIb/IIIa platelet membrane receptorantagonist antibody, recombinant hirudin and thrombin, thrombininhibitors such as Angiomax ä, calcium channel blockers such asnifedipine, colchicine, fish oil (omega 3-fatty acid), histamineantagonists, lovastatin, monoclonal antibodies such as those specificfor Platelet-Derived Growth Factor (PDGF) receptors, nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine, nitric oxide or nitric oxide donors, super oxidedismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO) andderivatives, analogs, prodrugs, codrugs and combinations thereof.

Examples of cytostatic agents include, without limitation, angiopeptin,angiotensin converting enzyme inhibitors such as captopril, cilazaprilor lisinopril, calcium channel blockers such as nifedipine; colchicine,fibroblast growth factor (FGF) antagonists, fish oil (ω-3-fatty acid),histamine antagonists, lovastatin, monoclonal antibodies such as,without limitation, those specific for Platelet-Derived Growth Factor(PDGF) receptors, nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist) andnitric oxide.

While several particular forms of the invention have been illustratedand described, it will also be apparent that various modifications canbe made without departing from the scope of the invention. It is alsocontemplated that various combinations or subcombinations of thespecific features and aspects of the disclosed embodiments can becombined with or substituted for one another in order to form varyingmodes of the invention. Accordingly, it is not intended that theinvention be limited, except as by the appended claims.

1. An implantable, intraluminal prosthesis comprising: a plurality ofinterconnected struts that form a tubular structure, each of the strutshaving a luminal surface facing radially inward and an abluminal surfacefacing radially outward, at least some of the struts havingthrough-holes with opposite end openings located at the abluminal andluminal surfaces, each of the through-holes having an inner surface witha geometric retention feature at a middle segment of the through-hole,the geometric feature having a predetermined shape corresponding to adistention of the through-hole or corresponding to a constriction of thethrough-hole; and a plurality of bioabsorbable depots, eachbioabsorbable depot carried in a separate one of the through-holes,wherein the geometric retention feature of each of the through-holes isconfigured to retain the bioabsorbable depot in the through-hole after adecrease in molecular weight, strength or mass of the bioabsorbabledepot.
 2. The prosthesis of claim 1, wherein the bioabsorbable depot ismade of a composition of a therapeutic agent mixed with a bioabsorbablepolymer.
 3. The prosthesis of claim 2, further comprising a coating on asurface of the tubular structure, the coating carrying a therapeuticagent that is the same as or different from the therapeutic agent of thebioabsorbable depot.
 4. The prosthesis of claim 1, wherein there is nodrug coating on any luminal surface and any abluminal surface of thetubular structure.
 5. The prosthesis of claim 1, wherein thethrough-holes are formed in a non-particulate substrate material of thestruts.
 6. The prosthesis of claim 1, wherein the geometric feature is aconstriction of the through-hole, and the constriction has across-dimension that is less a than cross-dimension of both end openingsof the through-hole.
 7. The prosthesis of claim 1, wherein the geometricfeature is a distension of the through-hole, and the distension has across-dimension that is greater than a cross-dimension of both endopenings of the through-hole.
 8. The prosthesis of claim 1, wherein theinner surface of each of the through-holes extends continuously from oneof the end openings to the other of the end openings, and the innersurface is convex.
 9. The prosthesis of claim 1, wherein the innersurface of each of the through-holes extends continuously from one ofthe end openings to the other of the end openings, and the inner surfaceis concave.
 10. The prosthesis of claim 1, wherein the geometricretention feature of each of the through-holes comprises a plurality ofgrooves formed into the inner surface of the through-hole.
 11. Theprosthesis of claim 1, wherein the geometric retention feature isdefined, at least in part, by stacked layers of a substrate material,each layer having a hole aligned with a hole of an immediately adjacentlayer, the hole of at least one of the layers defining a cross-dimensionof a distention or constriction of the through-hole.
 12. The prosthesisof claim 1, wherein the bioabsorbable depot comprises multiple layers ofbioabsorbable polymer, and any one or both of drug composition andpolymer composition varies among the multiple layers.
 13. The prosthesisof claim 1, wherein the bioabsorbable depot comprises multiple layers ofbioabsorbable polymer, and the bioabsorbable depot comprises drugs whichmay be in the same or different layers of the bioabsorbable polymer. 14.A implantable, intraluminal prosthesis comprising: a tubular frame ofinterconnected structural members, the tubular frame configured toexpand radially, at least some of the structural members having athrough-hole formed therein, each through-hole comprising two endopenings and an inner surface extending between the end openings, theinner surface having an indentation of a preselected size and shape; anda plurality of bioabsorbable depots, each bioabsorbable depot retainedin a separate one of the through-holes, each bioabsorbable depotcomprising a therapeutic agent and a bioabsorbable polymer, eachbioabsorbable depot comprising a protrusion that extends into theindentation of the through-hole in which the bioabsorbable depot isretained, the protrusion and the indentation engaged with each other toprevent the bioabsorbable depot from sliding out of at least one of theend openings.
 15. The prosthesis of claim 14, wherein every through-holehas a central axis that is substantially straight and radially oriented,and the central axis extends through the respective centers of the endopenings of the through-hole.
 16. The prosthesis of claim 15, whereinthe tubular frame has a central axis and each through-hole has anend-to-end length that is substantially perpendicular to the centralaxis.
 17. The prosthesis of claim 14, wherein the indentation is at amiddle segment of the through-hole.
 18. The prosthesis of claim 17,wherein the inner surface is concave.
 19. The prosthesis of claim 14,wherein the indentation is at one of the end openings of thethrough-hole.
 20. The prosthesis of claim 19, wherein the inner surfaceis convex.
 21. The prosthesis of claim 14, wherein the indentationextends entirely around a central axis of the through-hole, and thecentral axis extends through the respective centers of the end openingsof the through-hole.
 22. The prosthesis of claim 14, wherein thebioabsorbable polymer undergoes hydrolytic degradation upon implantationwithin a patient and the bioabsorbable polymer is located at middle andend segments of the bioabsorbable depot.
 23. A method of making animplantable, intraluminal prosthesis, the method comprising: forming atubular frame of interconnected structural members; formingthrough-holes in the structural members; forming an indentation in aninner surface of each of the through-holes; and forming a bioabsorbabledepot in each of the through-holes, comprising forming a protrusion ofthe bioabsorbable depot that engages the indentation of the through-holein which the bioabsorbable depot is retained, wherein engagement of theprotrusion with the indentation prevents the bioabsorbable depot fromsliding out an end opening of the through-hole.
 24. The method of claim23, wherein the forming of the through-holes is performed after theforming of the tubular frame, and the forming of the indentation isperformed after the forming of the through-holes.
 25. The method ofclaim 23, wherein the indentation is any one of a concave surface, aconvex surface, and a groove.
 26. The method of claim 23, wherein theforming of the through-holes comprises directing a laser toward thestructural members to form an end opening of one of the through-holes,followed by changing the orientation angle of the laser relative to thestructural members to form within the one of the through-holes adistended volume or a tapered inner surface.
 27. The method of claim 23,wherein the tubular frame and the through-holes are formed by stackinglayers of substrate material, each layer having a plurality of holesaligned with a plurality of holes of an immediately adjacent layer, theplurality of holes of at least one of the layers forming theindentations in the inner surfaces of the through-holes.